Theileria gets naked and rides the spindle

Hijacking of the cell by its uninvited invaders is one of the coolest things in biology. Not only do these parasites leech off its food, they also ride along with the cell machinery itself -- modifying parts of it for their own benefit, of course. Apicomplexans and microsporidia, obligate intracellular parasites during at least one stage of their life cycles, are among the masters of cytoterrorism* in the eukaryotic world.

*The NSA too should know about awesome parasites!

Apicomplexans live for cell invasion -- they're even named after their apical complex, a highly specialised machine fine tuned for penetrating its victims. They sort of look like torpedoes:

While wandering around a poster session at a conference last week, a particular poster reminded me of the existence of Theileria. Or, given how much thought I've given that bug, more like informed me about its existence. Theileriais a plague upon cattle in the tropical regions of Africa, and is an apicomplexan of the Piroplasmid affiliation. To orient ourselves in relation to the major apicomplexans studied, the agent of malaria, Plasmodium, is a Haemosporidian while felid-brain-ninja Toxoplasma is a a coccidian. Piroplasmids were traditionally considered a separate clade from them all, but are now found to be fairly close to Haemosporidians like Plasmodium (see 2011 tree in the apicomplexan ToLWeb page; tons of other good api' information there too).

Apicomplexans enjoy orgies in their primary host, which is usually an arthropod. The secondary host is merely a dispensable source of food, which is why parasites tend to be much crueler to the latter (eg. vertebrates like us, but sometimes plants too!). This is also why the two phases of the life cycle are rather different, given that their primary goals differ. Theileria's main secondary host (primary = ticks) is the water buffalo, who act as a reservoir due to their better resistance. Cattle, on the other hand, are outsiders, and far less capable of dealing with the African parasite. Theileria does not mind feasting on non-buffalo from time to time, but curiously -- strains are found in to specialise in different (and more susceptible) non-buffalo, but tend to be all found in the buffalo reservoir. It's like the strains usually hang out at the main party scene in the buffalo, but occasionally wander off on their own adventures. Sex, however, still happens in the tick. For the students of parasitology, remember: primary host = orgy, secondary host = food.

You're perfectly welcome to investigate Theileria's life cycle (figure), but I don't recommend it. Too many words and cell types.

This is the more or less 'typical' invasion strategy of apicomplexans, such Toxoplasma. In short, the parasite recognises a suitable cell surface to invade (through receptors and such), attaches itself, and begins to dig into the cell with its apical complex. As it invaginates the membrane inward, there is something akin to a sieve between the apical end of the parasite and the cell membrane, which removes the surface receptors of the host cell -- to avoid detection once inside. The apicomplexan glides through this sieve(=moving junction) and eventually the surrounding membrane buds off, leaving the parasite in its comfy customised vacuole inside the host. Then, as all parasites (and life in general), it feeds and breeds. Just to mess with us, Plasmodium -- which you'd think is 'typical' due to its importance to us (scientific logic!) -- and, yes, Theileria, have decided to do away with their conoids. The invasion process remains similar enough, luckily.

In the case of our more familiar apicomplexans, the parasite remains in its parasitophorous vacuole, until it blows up the host and escapes. Theileria, on the other hand, likes to get more intimate with its host -- sometime after a successful invasion, it sheds the parasitophorous vacuole altogether by dissolving its membrane. (Shaw 2003 Tr Parasitol) At this point, it immediately begins constructing a mitotic spindle out of tubulin (provided by the host cell, of course!) Toxoplasma, in contrast, divides while still inside its vacuole, only abandoning it after blowing up the host cell. This is improved further by Theileria dividing synchronously with the host cell, for months before the breakout occurs. The parasite goes in direct contact with the host cytoplasm and harnesses its subsequent generations for slavery, from within. Again, be glad you're not a cell -- although, there's a cornucopia of parasites who do this sort of thing with multicellulars -- eg. Cordyceps fungus, or the neuro-hijacking barnacle of crabs, Sacculina, who castrates the female crab and takes advantage of its parenting.

Back to Theileria. Since it lives synchronously with its host for a while, it would be preferable for it to segregate fairly evenly between the host daughter cells. The parasite spends its time there as a multinucleate plasmodium -- its own cycle still must be regulated as to not multiply its way out of the host cell and blow it up. This multinucleated parasite goo (mmm!) must then be split between the resultant pair of host cells. How they accomplish that was the focus of the study by von Schubert et al. 2013 PLoS Biol. Let's get a glimpse of what this looks like, below. The blue stains the DNA, both of the host and parasite -- those of the latter quite a bit smaller. The green highlights the parasite's cytoplasm, which you can follow through division. Finally, the red marks the microtubules, both cytoplasmic and those integrated in the spindle apparatus. Note how the spindle seems to be involved in not only segregating the host's chromosomes, but the parasite as well. The parasite even participates in the equatorial plate that defines metaphase, along with the chromosomes!

In the paper, they showed that its intimate interaction with the spindle is essential for Theileria to split itself properly between the host cells. Furthermore, some of the host cell's own proteins localised to the parasite -- suggesting a physical interaction between the host mitotic machinery and the parasite's own proteins (not too surprising for a parasite). Below is a 'fishing experiment' (sometimes a FISHing experiment, if hybridisation is involved, ahaha (reason behind most biology fish jokes)). They synchronised the cells by inhibiting one of the protein machines controlling the cell cycle progress, and then removing the drug to get the cells back into motion. Another drug was also added to prevent the host cell division furrow from happening. This allows to block cells just before cytokinesis and seeing what certain proteins are associated with.

Von Schubert et al. found one of the host's mitotic proteins the parasite hijacks, Polo-Like Kinase (PLK1). Plk-s are involved in starting mitosis and cytokinesis, from the beginning of chromosome condensation (prophase) to the division of the cell itself (has highschool or undergrad come to haunt you yet?). One of the "master regulators", so to speak (though not as mighty as CDKs and cyclins, the cell's "clock" proteins). PLK localises to Theileria's cell membrane, suggesting a close interaction between PLK and the parasite's own membrane proteins. Of course, as with everything in cell biology, this does not have to be direct -- what specifically PLK binds to (and what, in turn, that protein binds to... etc) remains to be determined. Nevertheless, this demonstrates a direct interaction between Theileria and the host cell division machinery. PLK is associated with the chromosomal centromeres, so in a way, it appears that Theileria can pretend to be just another set of chromosomes.

Localisation patterns of PLK and one of Theileria's surface proteins just before (G2), at the beginning, and at towards the end of mitosis. DNA is in blue. Yellow shows colocalisation (presence in the same area) between green and red signal -- ie, PLK1 and Theileria's SP1. Curiously, it's absent from the parasite during prometaphase (middle), but then returns back to the surface. It doesn't appear to be known why quite yet. (Modified from von Schubert et al. 2013 PLoS Biol fig 2).

Theileria not only exposes itself upon invading its slave, but directly binds to the mitotic spindle to segregate. In a similar manner, Toxoplasma takes advantage of the host centriole, but has an extra membrane between itself and the host's mitotic stuff, thus the binding is much more indirect. You gotta be naked to properly ride a spindle. The authors have a great summary below, and I've only scratched the surface of the cell biology work they've done on this wonderful organism. I recommend checking it out, at least for the pretty microscopy.

Synchronisation with -- or detection of in general -- the host's cell cycle is an important puzzle in the life of many parasites. Fun fact: the periodic flashes of fever that accompany malaria result from Plasmodium escaping their host blood cells all at once, to quickly burrow into their next victims (eg. Mideo et al. 2013 [paywalled]). This completely overwhelms the immune system! Basically, a deadlier variant of periodical cicadas. Just as with the cicadas, a tantalising question lingers -- just how do they figure out the timing? Despite the incredible variety of different infection and replication strategies of apicomplexans, shown below for no other purpose but microscopy porn, they all have some interaction with their victim, and must time their attacks accordingly. Personally, I find that absolutely amazing!

A 'convenient' feature of global warming is that tropical diseases are starting to migrate northward. For example, it seems that typically-tropical Trypanosoma cruzi, the cause of Chagas Disease (which leads to heart muscles becoming replaced by the parasite -- lovely!), is becoming more and more prevalent in the American South. This is great news -- for neglected tropical diseases research. Many of them are caused by protists, so hopefully interest in protists -- but more importantly, non-northern diseases that don't affect the Western world as much -- will increase and attract funding. Besides, don't forget that much of the American South and Southeast (including Washington DC), is traditionally home to malaria. We are not as inherently free of Plasmodium as we wish to think. Someday, it may well be that Theileria, Nagana, and African Sleeping Sickness are no longer "just" an African problem. Maybe that, rather than basic humanity, will be enough to begin seriously investigating prevention and cure of those nasty afflictions.

Curing people of parasites, of course -- but also learning more about the many ways in which they are biologically awesome. Like the coat-less, spindle-hijacking Theileria.

The views expressed are those of the author and are not necessarily those of Scientific American.

Share this Article:

Comments

Welcome to the Scientific American Blog Network, a forum for a diverse and independent set of voices to share news and opinions and discuss issues related to science. For more information see our About page and Guidelines....more